Sphingosine is a product of sphingolipid metabolism that has been linked to a protein kinase C-independent mitogenic response. In previously published data, utilizing an in vitro model system for platelet-derived growth factor (PDGF)-induced vascular smooth muscle proliferation, we have demonstrated that sphingosine is increased at the expense of a concomitant decrease in ceramide formation, implicating an altered ceramidase activity. To explore mechanisms of growth factor-stimulated sphingosine formation, we have developed and investigated a cell-free model system assessing ceramidase activity. We now report that an alkaline, membrane-associated, ceramidase activity in the rat glomerular mesangial cell, a smooth muscle-like pericyte, is up-regulated by growth factors, apparently via a tyrosine kinase phosphorylation mechanism. PDGF also stimulated sphingomyelinase activity which generates sufficient substrate to drive the subsequent ceramidase reaction. Inflammatory cytokines, including interleukin-1, and tumor necrosis factor-␣, stimulated sphingomyelinase but not ceramidase activity, a result consistent with the cellular accumulation of the ceramide, apoptidic, differentiating second messenger. Mitogenic vasoconstrictor peptides such as endothelin-1 stimulated neither sphingomyelinase nor ceramidase activities. An inhibitor of ceramidase activity, N-oleoylethanolamine, reduced PDGF-but not endothelin-1-stimulated proliferation. Thus, we conclude that, in mesangial cells, growth factors but not vasoconstrictor peptides or cytokines induce mitogenesis, in part, through ceramidase-mediated sphingosine formation.Sphingolipids are complex ubiquitous lipids that have been relegated to serving a structural role in membranes. Sphingolipids are characterized as consisting of a long chain amino dialcohol base (sphingoid), an amide-linked fatty acyl group, and a polar or glycosidic head group. Over the last few years, sphingolipid derivatives have been identified as endogenous membrane signal-transducing molecules. Sphingomyelin, the major membrane sphingolipid, can be hydrolyzed by sphingomyelinase to form ceramide, a second messenger which stimulates differentiation, inhibits proliferation, and has been associated with apoptosis (1, 2). Several cytokines and steroids have been shown to stimulate sphingomyelinase and form ceramide.Tumor necrosis factor-␣ (TNF-␣), 1 interleukin-1␤, ␥-interferon, and 1␣,25-dihydroxy vitamin D 3 activate sphingomyelinase in hematopoietic cell lines (3-5). The sphingomyelin signaling pathway stimulated by TNF-␣ and interleukin-1␤ can be reconstituted in cell-free extracts (4, 6) and may be mediated by arachidonic acid (7). Ceramides are themselves substrates for ceramidases that form the promitogenic lipid, sphingosine (8). Our laboratory and the laboratory of Spiegel have recently reported that platelet-derived growth factor (PDGF) stimulates mitogenic, sphingolipid-derived, second messengers including sphingosine and sphingosine-1-phosphate by degrading ceramide (9, 10). These data are c...

Highlights d Stem cell-derived glioma formation is accompanied by loss of neurogenesis d miR-124-dependent neuronal differentiation reduces glioblastoma (GBM) aggressiveness d An ERK1/2-miR-124-SOX9 axis regulates neuronal differentiation in GBM cells d An miR-124-induced neuronal phenotype sensitizes GBM cells to radiation

We accept the hypothesis that temporary renal ischemia leads to a significantly increased radiofrequency ablation lesion size. We conclude that catheter-based balloon perfusion reduction is feasible, that the procedure does not lead to major complications, and that it can be performed using MR imaging as the sole imaging modality.